Document Detail

Characterization of a novel CRAC inhibitor that potently blocks human T cell activation and effector functions.
MedLine Citation:
PMID:  23357789     Owner:  NLM     Status:  Publisher    
Store operated calcium entry (SOCE) downstream of T cell receptor (TCR) activation in T lymphocytes has been shown to be mediated mainly through the Calcium Release Activated Calcium (CRAC) channel. Here, we compared the effects of a novel, potent and selective CRAC current inhibitor, 2,6-Difluoro-N-{5-[4-methyl-1-(5-methyl-thiazol-2-yl)-1,2,5,6-tetrahydro-pyridin-3-yl]-pyrazin-2-yl}-benzamide (RO2959), on T cell effector functions with that of a previously reported CRAC channel inhibitor, YM-58483, and a calcineurin inhibitor Cyclosporin A (CsA). Using both electrophysiological and calcium-based fluorescence measurements, we showed that RO2959 is a potent SOCE inhibitor that blocked an IP(3)-dependent current in CRAC-expressing RBL-2H3 cells and CHO cells stably expressing human Orai1 and Stim1, as well as SOCE in human primary CD4(+) T cells triggered by either TCR stimulation or thapsigargin treatment. Furthermore, we demonstrated that RO2959 completely inhibited cytokine production as well as T cell proliferation mediated by TCR stimulation or MLR (mixed lymphocyte reaction). Lastly, we showed by gene expression array analysis that RO2959 potently blocked TCR triggered gene expression and T cell functional pathways similar to CsA and another calcineurin inhibitor FK506. Thus, both from a functional and transcriptional level, our data provide evidence that RO2959 is a novel and selective CRAC current inhibitor that potently inhibits human T cell functions.
Gang Chen; Sandip Panicker; Kai-Yeung Lau; Subramaniam Apparsundaram; Vaishali A Patel; Shiow-Ling Chen; Rothschild Soto; Jimmy K C Jung; Palanikumar Ravindran; Dayne Okuhara; Gary Bohnert; Qinglin Che; Patricia E Rao; John D Allard; Laura Badi; Hans-Marcus Bitter; Philip A Nunn; Satwant K Narula; Julie A Demartino
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-25
Journal Detail:
Title:  Molecular immunology     Volume:  54     ISSN:  1872-9142     ISO Abbreviation:  Mol. Immunol.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-29     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7905289     Medline TA:  Mol Immunol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  355-367     Citation Subset:  -    
Copyright Information:
Copyright © 2012 Elsevier Ltd. All rights reserved.
Inflammation Discovery, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA. Electronic address:
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